DOI: 10.20935/acadneurosci8396 ISSN: 3071-4087

Creatine monohydrate and neuronal methylation in psychiatric disorders

Liesl Strydom, Khethelo R. Xulu
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Mental health and neurodevelopmental disorders, such as psychotic disorders, depression, anxiety, and autism spectrum disorder, are characterised by complex gene–environment interactions and epigenetic dysregulation. These disorders represent a profound and growing societal burden on health systems. Creatine monohydrate has been suggested to have cognitive benefits in neurodegenerative contexts but lacks a mechanistic framework for application in earlier-onset neuropsychiatric conditions. Here, we propose a novel hypothesis that creatine monohydrate may act as a stabiliser of DNA methylation dynamics by targeting the metabolic–epigenetic interface in the brain. We theorise that creatine operates via two synergistic pillars to support methylation homeostasis. First, through bioenergetic stabilisation, it boosts the phosphocreatine (PCr) system, ensuring adequate adenosine triphosphate (ATP) for synaptic function and, critically, for ATP-dependent chromatin-remodelling complexes SWItch/sucrose non-fermentable (SWI/SNF), imitation SWItch (ISWI), chromodomain helicase DNA-binding (CHD), and inositol requiring 80 (INO80) families that regulate chromatin accessibility. DNA methyltransferases (DNMTs), which catalyse cytosine methylation, are S-adenosyl-L-methionine (SAM)-dependent rather than directly ATP-coupled at the catalytic step; ten-eleven translocation 1, 2, and 3 (TET1/2/3) dioxygenases require α-ketoglutarate and Fe2+ as co-substrates. The ATP argument therefore applies principally to chromatin-remodelling ATPases and to proteostatic machinery. Second, by modulating the methyl cycle, exogenous creatine suppresses endogenous synthesis by feedback inhibition of the enzyme guanidinoacetate N-methyltransferase (GAMT). This “methyl-sparing” effect conserves S-adenosylmethionine (SAM) and lowers S-adenosylhomocysteine (SAH) and is thereby predicted to promote a SAM/SAH ratio conducive to balanced methylation dynamics. This dual mechanism does not correct primary genetic lesions but instead is proposed to create a cellular environment that buffers against the downstream consequences of epigenetic dysregulation, enhancing neuronal resilience. The hypothesis generates testable, multi-scale predictions: supplementation is predicted to (1) increase the cerebral PCr/ATP ratio and alter plasma SAM/SAH, (2) reduce global DNA methylation variance and potentially normalise specific synaptic gene promoter methylation such as brain-derived neurotrophic factor (BDNF), methyl-CpG-binding protein 2 (MECP2) and improve cognitive and behavioural outcomes correlated with these biomarker shifts. By linking basic biochemistry to systems-level neuropsychiatric pathophysiology, this theory provides a unified rationale for repurposing creatine monohydrate. It underscores the therapeutic potential of supporting core cellular physiology to stabilise complex brain disorders.

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